Idiopathic hypogonadotropic hypogonadism (IHH) is due to a deficiency of GnRH. The major goal of this proposal is to isolate the gene(s) important in the genesis of IHH. In the hypogonadal mouse, hypogonadotropic hypogonadism is due to a GnRH gene deletion, but no GnRH gene mutations have been identified in humans with IHH. Except for two X-linked disorders, Kallmann's syndrome, consisting of IHH and anosmia (KAL mutations) and hypogonadotropic hypogonadism associated with congenital adrenal hyperplasia (DAX-1 gene mutations), the etiology of IHH remains unknown. This project will attempt to identify affected individuals with IHH and to isolate candidate genes utilizing new approaches. The first specific aim will be to increase the number of IHH families in the database.
The second aim will be to better characterize the phenotype of IHH patients based upon physical exam, endocrinologic studies, and pedigree structure.
The third aim will be to use linkage analysis, linkage disequilibrium analysis, and association to identify candidate genes which might be involved in the pathogenesis of IHH. The identification of new genes is important for control of reproduction has tremendous implications for the treatment of pubertal disorders, infertility, and potentially contraception. Depending upon the types of mutations characterized, molecular diagnosis might be possible for children with delayed puberty. Female and male humans with idiopathic hypogonadotropic hypogonadism (IHH) typically present with delayed puberty, low serum gonadotropins, and the absence of pituitary dysfunction and tumor. Current endocrinologic evidence suggests that IHH is due to a deficiency of gonadotropin releasing hormone (GnRH), although heterogeneity exists in clinical, endocrinologic, and genetic attributes of the disorder. The hypogonadal mouse has hypogonadotropic hypogonadism due to a GnRH gene deletion, but no GnRH gene mutations have been identified in humans with IHH. Except for two X-linked disorders, Kallmann syndrome, consisting of IHH and anosmia (KAL gene mutations), and hypogonadotropic hypogonadism associated with congenital adrenal hypoplasia (DAX-1 gene mutations), the etiology of IHH remains unknown. The major goal of this proposal is to isolate genes important in the genesis of IHH.
Our specific aims are: (1) To increase our number of IHH families; (2) to better characterize the phenotype of IHH patients based upon physical exam, endocrinologic studies, and pedigree structure; and (3) to use linkage, linkage disequilibrium, and association to test candidate genes which might be involved in the pathogenesis of IHH. Despite genetic heterogeneity, these genetic analyses provide important information for gene mapping. Although IHH is not a common disorder, it has certain important characteristics which make the understanding of its pathophysiology important since it affects puberty and reproduction in both sexes. The identification of new genes important in reproduction has tremendous implications for treatment of pubertal disorders, infertility, and potentially contraception. If a new gene is identified, a better understanding of IHH, and perhaps more importantly, normal reproduction, will be gained. Depending upon the types of mutations characterized, molecular diagnosis might be possible for children with delayed puberty. New therapies for the treatment of delayed puberty and infertility might also be possible once the protein structure and function are better understood. Potentially, contraceptive technologies could be developed based upon the understanding of the function of newly identified genes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HD033004-05
Application #
6181701
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Taymans, Susan
Project Start
1999-07-15
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
5
Fiscal Year
2000
Total Cost
$105,120
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Kim, Yeon-Joo; Osborn, Daniel Ps; Lee, Ji-Young et al. (2018) WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome. EMBO Rep 19:269-289
Demir Eksi, Durkadin; Shen, Yiping; Erman, Munire et al. (2018) Copy number variation and regions of homozygosity analysis in patients with M√úLLERIAN aplasia. Mol Cytogenet 11:13
Williams, Lacey S; Demir Eksi, Durkadin; Shen, Yiping et al. (2017) Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families. Fertil Steril 108:145-151.e2
Williams, Lacey S; Kim, Hyung-Goo; Kalscheuer, Vera M et al. (2016) A balanced chromosomal translocation involving chromosomes 3 and 16 in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome reveals new candidate genes at 3p22.3 and 16p13.3. Mol Cytogenet 9:57
Choi, Jin-Ho; Balasubramanian, Ravikumar; Lee, Phil H et al. (2015) Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. J Clin Endocrinol Metab 100:E1378-85
Quaynor, Samuel D; Goldberg, Lindsey Y; Ko, Eun Kyung et al. (2014) Differential expression of nasal embryonic LHRH factor (NELF) variants in immortalized GnRH neuronal cell lines. Mol Cell Endocrinol 383:32-7
Newbern, Kayce; Natrajan, Nithya; Kim, Hyung-Goo et al. (2013) Identification of HESX1 mutations in Kallmann syndrome. Fertil Steril 99:1831-7
Layman, Lawrence C (2013) Clinical genetic testing for Kallmann syndrome. J Clin Endocrinol Metab 98:1860-2
Layman, Lawrence C (2013) The genetic basis of female reproductive disorders: etiology and clinical testing. Mol Cell Endocrinol 370:138-48
Siegel, Eric T; Kim, Hyung-Goo; Nishimoto, Hiromi Koso et al. (2013) The molecular basis of impaired follicle-stimulating hormone action: evidence from human mutations and mouse models. Reprod Sci 20:211-33

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